title: Regulation of estrogen receptor α by histone methyltransferase SMYD2-mediated protein methylation.
abstract: Estrogen receptor alpha (ERα) is a ligand-activated transcription factor. Upon estrogen stimulation, ERα recruits a number of coregulators, including both coactivators and corepressors, to the estrogen response elements, modulating gene activation or repression. Most coregulator complexes contain histone-modifying enzymes to control ERα target gene expression in an epigenetic manner. In addition to histones, these epigenetic modifiers can modify nonhistone proteins including ERα, thereby constituting another layer of transcriptional regulation. Here we show that SET and MYND domain containing 2 (SMYD2), a histone H3K4 and H3K36 methyltransferase, directly methylates ERα protein at lysine 266 (K266) both in vitro and in cells. In breast cancer MCF7 cells, SMYD2 attenuates the chromatin recruitment of ERα to prevent ERα target gene activation under an estrogen-depleted condition. Importantly, the SMYD2-mediated repression of ERα target gene expression is mediated by the methylation of ERα at K266 in the nucleus, but not the methylation of histone H3K4. Upon estrogen stimulation, ERα-K266 methylation is diminished, thereby enabling p300/cAMP response element-binding protein-binding protein to acetylate ERα at K266, which is known to promote ERα transactivation activity. Our study identifies a previously undescribed inhibitory methylation event on ERα. Our data suggest that the dynamic cross-talk between SMYD2-mediated ERα protein methylation and p300/cAMP response element-binding protein-binding protein-dependent ERα acetylation plays an important role in fine-tuning the functions of ERα at chromatin and the estrogen-induced gene expression profiles.
authors.affiliation: Departments of Biochemistry and Molecular Biology and Anesthesiology and Perioperative Medicine and Centers for Cancer Epigenetics, Stem Cell and Developmental Biology, and Genetics and Genomics, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Kaori
authors.initials: K
authors.lastname: Tanaka
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Yan
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Danni
authors.initials: D
authors.lastname: Peng
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Barton
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D056466:Histone Demethylases / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008745:Methylation / Q000187:drug effects; D009154:Mutation; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D002843:Chromatin; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C495195:KDM1A protein, human; C512569:SMYD2 protein, human
keywords: ERα hinge region; LSD1; lysine methylation